The compositions disclosed herein, in general, relate to pharmaceutical compositions containing a bifunctional alkylating agent. More particularly, the compositions disclosed herein relate to stable, pharmaceutically acceptable compositions prepared from bendamustine. Furthermore, the method disclosed herein relates to preparation of such compositions for treating a condition in a subject in need thereof.
Bendamustine is a drug that was first synthesized in the 1960s with high potency in the treatment of several tumoral diseases and has been in clinical use since 1985. Bendamustine functions as a bifunctional alkylating agent with antimetabolic and cytotoxic activity indicated for treatment of subjects with chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab containing regimen. Efficacy relative to first line therapies other than a chlorambucil drug used in the treatment of CLL has not been established. A molecule of bendamustine comprises three structural elements, namely, a mechlorethanamine group, a benzimidazole core, and a butyric acid chain. The butyric acid chain together with a protonated heterocycle mediates water solubility. The benzimidazole moiety should lead to tumor cell accumulation by purine base transporters.
Bendamustine was developed in the 1960s by East German pharmacologists with an aim of combining a 2-chloroethylamine group of nitrogen mustard derivatives with a benzimidazole ring system of purine analogues. Bendamustine entered clinical trial in 1969 to treat multiple myeloma (MM) and entered the German market in the early 1970s. Bendamustine was marketed in Germany from 1971 to 1992 as Cytostasan and from 1993 to present as Ribomustin. Because of the high reactivity of bendamustine in aqueous solutions, nitrogen mustards are difficult to formulate as pharmaceuticals and are often supplied for administration in a lyophilized form. The lyophilized form of bendamustine requires reconstitution, typically in water, by skilled medical personnel prior to administration. Once in an aqueous solution, nitrogen mustards are subject to degradation by hydrolysis and therefore the reconstituted product should be administered to a subject as soon as possible after reconstitution.
Reconstitution of a powdered lyophilized bendamustine product such as Ribomustin using existing reconstitution techniques is difficult. Typically, the reconstitution time for the lyophilized bendamustine product varies from about fifteen minutes to about thirty minutes. The level of impurities in the lyophilized bendamustine product manufactured using water and various solvent mixtures is about 0.9 wt % after reconstitution. Porous lyophilized bendamustine generated using a solvent and a water mixture has a lesser reconstitution time of about 3 minutes to about 10 minutes as compared to the commercially available Ribomustin which takes about fifteen minutes to about thirty minutes to reconstitute. However, a reconstitution time of even 3 minutes to 10 minutes generates high impurity levels in the lyophilized bendamustine product. Moreover, as manufacture of the lyophilized bendamustine product involves organic solvents, making the final product free from solvents is difficult. Furthermore, environmental and safety implications are difficult to control during commercial manufacture of the bendamustine product. In 2005, after formal clinical development programs were conducted in the USA and in Europe, the bendamustine product was made available for use in the USA and United Kingdom (UK) under the trade names Treanda® by Cephalon, Inc., and Levact® by Mundipharma AG, respectively. However, many of the issues mentioned above still remain with these products.
The drug Treanda® is intended for intravenous infusion into subjects suffering from tumoral diseases only after reconstitution with sterile water for injection in United States Pharmacopeia (USP) unit, and after further dilution with either 0.9 wt % sodium chloride injection in USP unit, or 2.5 wt % dextrose/0.45 wt % sodium chloride injection in USP unit. The drug Treanda® is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single use vial. Each 25 mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol in USP unit. Each 100 mg vial comprises 100 mg of bendamustine hydrochloride and 170 mg of mannitol in USP unit. The pH of the reconstituted solution is 2.5 to 3.5. As per the package insert of the drug Treanda®, the vial comprising the drug Treanda® should be aseptically reconstituted as follows: for a 25 mg vial comprising the drug Treanda®, 5 mL of only sterile water is added for injection in USP unit; for a 100 mg vial comprising the drug Treanda®, 20 mL of only sterile water is added for injection in USP unit. The vial should then be shaken well to yield a clear, colorless to a pale yellow solution with a bendamustine hydrochloride concentration of 5 mg/mL. As per the package insert, the lyophilized product should completely dissolve in 5 minutes. Though the drug Treanda® has shown a relatively smaller reconstitution time compared to its predecessor, 5 minutes is still a significant time for reconstitution which can generate higher impurities considering the instability of the drug Treanda®.
Hence, there is a long felt but unresolved need for lyophilized formulations of bendamustine hydrochloride that do not use non-aqueous solvents as part of the bendamustine hydrochloride composition or its formulation process. Moreover, there is a need for a method for preparing a stable lyophilized bendamustine hydrochloride composition that reconstitutes easily, yields a better impurity profile than the existing bendamustine product, takes a shorter time to administer to a subject in need thereof than bendamustine hydrochloride products in the market, and makes the composition more physician or nurse friendly.